Several publications are referenced in this application by author name, year and journal of publication in parentheses in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these publications is incorporated by reference herein.
Human Immunodeficiency Virus Type-1 (HIV-1)-associated dementia (HAD) is the result of cumulative pathogenic insults that ultimately affect brain synaptic function and neuronal death resulting in cognition and memory impairments. The mechanism by which functional changes occur in neurons during disease remains unknown. Nonetheless, neural injury correlates with immune activation of brain mononuclear phagocytes (MPs; infiltrating perivascular macrophages and resident brain macrophages or microglia). MPs are key mediators of central nervous system (CNS) inflammation. It is these cells that are recruited in response to trauma (12), infection, autoimmune reactions (11), and toxin (metabolic/drug) related injury (17). In the presence of an ongoing inflammatory response, both infiltrating macrophages and endogenous microglia become immune-activated. Activated MPs recruit additional leukocytes to sites of tissue injury and engage in a wide range of secretory activities. Such events may be mediated through chemokines and/or other inflammatory mediators that promote cellular adhesion and brain leukocyte infiltration. Importantly, MPs are capable of altering neuronal function/viability by disrupting the delicate homeostatic balance of the CNS microenvironment. Activated MP can generate cytotoxic factors that perpetuate paracrine-amplified inflammation (1, 4) leading to neuronal injury and loss.
The mechanism by which MPs become activated in the brain remains poorly understood but several lines of evidence indicate biochemical communication between the central nervous system and the immune system. It is likely that certain mechanisms involved in the CNS response to systemic immune challenge cause brain inflammation. Up- or down-regulation of gene expression of specific MP genes appears to mediate this process, leading to the culmination of a neurotoxic response and disease progression. Mammals have about 100,000 different genes, approximately 30,000 of which are thought to be expressed in the brain (21). Controlled regulation of gene expression ensures that small fractions of these genes are expressed in individual brain cells, gene expression being related to particular brain cell functions. It has been hypothesized that the pathological changes that arise in HAD are driven by aberrant changes in this regulated gene expression.
As those skilled in the treatment of HAD appreciate, a need exists for improved therapeutic agents for the treatment of this disorder.